Natural killer (NK) cells constitute about 10% of peripheral blood lymphocytes. They kill virus-infected cells and tumor cells through engagement of an array of germ-line encoded activation receptors. In addition to their innate ability to eliminate transformed and infected cells, NK cells perform antibody-dependent cellular cytotoxicity (ADCC) through the low affinity IgG receptor FcgammaRIIIa (also known as CD16), thereby killing IgG-coated target cells and secreting pro-inflammatory cytokines such as IFN-gamma. Plasmodium falciparum, the causative agent of malaria, expresses proteins that are displayed at the surface of infected red blood cells (RBC). Some of these proteins promote sequestration of P. falciparum-infected RBC through adhesion to vascular endothelial cells. Humans living in malaria-endemic areas generate, over years of repeated infections, antibodies to P. falciparum proteins that contribute to the gradual protection from malaria symptoms. One of the main objectives in malaria research is to define the mechanisms by which naturally acquired antibodies provide protection. Neutralizing antibodies that prevent P. falciparum merozoite invasion of RBC have been described. However, as merozoites released from late-stage infected RBC rapidly invade uninfected RBC, high antibody titers are needed for inhibition. Antibodies bound to infected RBC promote phagocytosis by myeloid cells, and antibodies bound to merozoites activate the complement pathway. A clear role of NK cells in contributing to protection from malaria, and whether iRBCs could be eliminated through ADCC by NK cells, have not been established. We have shown that IgG isolated from adults living in a malaria-endemic region activated ADCC by primary human NK cells, which lysed infected RBC and inhibited parasite growth in an in vitro assay for ADCC-dependent growth inhibition. RBC lysis by NK cells was highly selective for infected RBCs in a mixed culture with uninfected RBC. As these results implicate acquired immunity through NK-mediated ADCC, antibody-based vaccines that target bloodstream parasites should consider this new mechanism of action. We evaluated the phenotypic and functional attributes of NK cells in people living in a malaria-endemic region and examined whether particular subsets correlated with protection during P. falciparum infection. Phenotypic markers for 'adaptive' NK cells were also included. Adaptive, or 'memory-like', NK cells were first described in cytomegalovirus (CMV)-infected individuals. CMV-associated human adaptive NK cells can broadly be defined as CD56dim cells that have lost expression of the transcription factor PLZF and lack expression of the signaling proteins FcR gamma chain through epigenetic changes. We determined the phenotype and function of natural killer (NK) cells, with a particular focus on antibody-dependent cellular cytotoxicity (ADCC), in a cohort of subjects living in a malaria-endemic region of Mali. Multi-parameter flow cytometry revealed a high frequency of adaptive NK cells, which are defined by the loss of transcription factor PLZF and Fc receptor signaling subunit gamma. These adaptive NK cells exhibited strong FcgammaRIIIa-mediated ADCC, which increased even further during acute malaria episodes. The relative frequency of FcR gamma-negative NK cells within the total NK cell population correlated with lower parasitemia and resistance to malaria symptoms. Malaria-susceptible subjects with the largest increase of the PLZF-negative subset of NK cells through the malaria transmission season had improved odds of being protected from symptomatic malaria during the subsequent malaria season. NK cells from Malian subjects were activated by addition of plasma from malaria-resistant individuals to P. falciparum-infected red blood cells. These findings implicate adaptive NK cell-mediated ADCC toward P. falciparum-infected red blood cells as a mechanism of acquired immunity to malaria. Consideration of P. falciparum antigens exposed on red blood cells as vaccine targets, and of NK cell ADCC as readout for efficacy, is therefore warranted in the design of malaria vaccines.